Endometrial carcinoma recurrence according to race and ethnicity: An NRG Oncology/Gynecologic Oncology Group 210 Study.

Non-Hispanic black (NHB) women are more likely to experience an endometrial carcinoma (EC) recurrence compared to non-Hispanic white (NHW) women. The extent to which tumor characteristics, socioeconomic status (SES) and treatment contribute to this observation is not well defined. In the NRG Oncology/Gynecology Oncology Group (GOG) 210 Study we evaluated associations between race/ethnicity and EC recurrence according to tumor characteristics with adjustment for potential confounders. Our analysis included 3,199 NHW, 532 NHB and 232 Hispanic women with EC. Recurrence was documented during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between race/ethnicity and EC recurrence in models stratified by histologic subtype (low-grade endometrioid, high-grade endometrioid, serous, mixed cell, carcinosarcoma, clear cell) or stage (I, II, III) and adjusted for age, SES, body mass index, smoking status and treatment. In histologic subtype-stratified models, higher EC recurrence was noted in NHB women with low-grade endometrioid (HR = 1.94, 95% CI = 1.21-3.10) or carcinosarcomas (HR = 1.66, 95% CI = 0.99-2.79) compared to NHWs. In stage-stratified models, higher EC recurrence was noted among NHB women with stage I (HR = 1.48, 95% CI = 1.06-2.05) and Hispanic women with stage III disease (HR = 1.81, 95% CI = 1.11-2.95). Our observations of higher EC recurrence risk among NHB and Hispanic women, as compared to NHW women, were not explained by tumor characteristics, SES, treatment or other confounders. Other factors, such as racial differences in tumor biology or other patient factors, should be explored as contributors to racial disparities in EC recurrence.

Metastatic breast tumors express increased tau, which promotes microtentacle formation and the reattachment of detached breast tumor cells.

The cytoskeletal organization of detached and circulating tumor cells (CTCs) is currently not well defined and may provide potential targets for new therapies to limit metastatic tumor spread. In vivo, CTCs reattach in distant tissues by a mechanism that is tubulin-dependent and suppressed by polymerized actin. The cytoskeletal mechanisms that promote reattachment of CTCs match exactly with the mechanisms supporting tubulin microtentacles (McTN), which we have recently identified in detached breast tumor cells. In this study, we aimed to investigate how McTN formation is affected by the microtubule-associated protein, tau, which is expressed in a subset of chemotherapy-resistant breast cancers. We demonstrate that endogenous tau protein localizes to McTNs and is both necessary and sufficient to promote McTN extension in detached breast tumor cells. Tau-induced McTNs increase reattachment of suspended cells and retention of CTCs in lung capillaries. Analysis of patient-matched primary and metastatic tumors reveals that 52% possess tau expression in metastases and 26% display significantly increased tau expression over disease progression. Tau enrichment in metastatic tumors and the ability of tau to promote tumor cell reattachment through McTN formation support a model in which tau-induced microtubule stabilization provides a selective advantage during tumor metastasis.

Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan.

Classifying endometrial hyperplasia (EH) according to the severity of glandular crowding (simple hyperplasia (SH) vs complex hyperplasia (CH)) and nuclear atypia (simple atypical hyperplasia (SAH) vs complex atypical hyperplasia (CAH)) should predict subsequent endometrial carcinoma risk, but data on progression are lacking. Our nested case-control study of EH progression included 138 cases, who were diagnosed with EH and then with carcinoma (1970-2003) at least 1 year (median, 6.5 years) later, and 241 controls, who were individually matched on age, date, and follow-up duration and counter-matched on EH classification. After centralised pathology panel and medical record review, we generated rate ratios (RRs) and 95% confidence intervals (CIs), adjusted for treatment and repeat biopsies. With disordered proliferative endometrium (DPEM) as the referent, AH significantly increased carcinoma risk (RR=14, 95% CI, 5-38). Risk was highest 1-5 years after AH (RR=48, 95% CI, 8-294), but remained elevated 5 or more years after AH (RR=3.5, 95% CI, 1.0-9.6). Progression risks for SH (RR=2.0, 95% CI, 0.9-4.5) and CH (RR=2.8, 95% CI, 1.0-7.9) were substantially lower and only slightly higher than the progression risk for DPEM. The higher progression risks for AH could foster management guidelines based on markedly different progression risks for atypical vs non-atypical EH.

Metastatic breast lobular carcinoma involving tamoxifen-associated endometrial polyps: report of two cases and review of tamoxifen-associated polypoid uterine lesions.

Two cases of lobular breast carcinoma metastatic to an endometrial polyp are described. Both patients had been treated with tamoxifen and presented with abnormal uterine bleeding. Histology of endometrial biopsy in both cases showed typical tamoxifen-associated endometrial polyps with focal subtle stromal infiltration by metastatic lobular breast carcinoma. This was confirmed by positive immunohistochemical staining with cytokeratin epithelial markers. Metastatic breast carcinoma may rarely involve tamoxifen-associated endometrial polyps. Because primary endometrial carcinomas may also arise within tamoxifen polyps, these should be extensively sampled. We briefly review polypoid uterine lesions that may occur secondary to tamoxifen therapy.

Absence of SV-40 large T antigen (Tag) in malignant mesothelioma effusions: an immunocytochemical study.

Simian Virus 40 (SV 40) was recently implicated in the pathogenesis of malignant mesothelioma. The oncogenic capacity of SV-40 is a function of a nuclear protein, the large T antigen (Tag). SV-40 Tag DNA sequences are detected by the polymerase chain reaction in 40-80% of malignant mesothelial proliferations. However, the role of immunohistochemistry (IHC) in demonstrating the nuclear localization of Tag is controversial. We sought to determine the clinical utility of SV-40 Tag IHC in pleural effusion cytology as an ancillary tool in the cytologic diagnosis of malignant mesothelioma (MM). Formalin-fixed, paraffin-embedded cell block sections from 100 pleural effusions (32 MMs, 25 benign reactive, 43 metastatic adenocarcinomas) were immunostained for the SV-40 anti-Tag, using two primary monoclonal SV-40 Tag antibodies: clone Pab 416 and clone Pab 101. Despite strong and consistent immunoreactivity in positive controls, no nuclear immunostaining was observed in any case. We believe the small sample size in cytology cell block sections, the low viral copy number in infected cells, and the effect of formalin fixation may have resulted in absence of immunoreactivity. The role of SV-40 Tag IHC in diagnostic cytopathology remains unclear unless further studies reliably show its detection.

Atypical lobular hyperplasia or lobular carcinoma in situ at core-needle breast biopsy.

PURPOSE: To review outcomes of lesions diagnosed at core-needle breast biopsy as atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS). MATERIALS AND METHODS: Results from 1,400 consecutive core-needle breast biopsies were reviewed. Twenty-five (1.8%) biopsy samples with the diagnosis of lobular neoplasia (15 with ALH and 10 with LCIS) adjacent to or in a targeted benign lesion were found. Lesions were excised (n = 15) or followed up (n = 10) at least 22 months. RESULTS: Of the 15 lesions with ALH, 13 (87%) were adjacent to (n = 12) or associated with (n = 1) microcalcifications, and two (13%) were in masses. Six lesions with residual calcifications were excised. One lesion was diagnosed as ductal carcinoma in situ (DCIS), and five were benign (residual ALH was seen in four). One excised mass showed residual ALH. Six lesions were gone at follow-up, one cluster of microcalcifications was decreased in size, and one fibroadenoma with ALH was stable. Of the 10 lesions with LCIS, seven (70%) were adjacent to (n = 6) or associated with (n = 1) microcalcifications, and three (30%) were in or adjacent to masses. Five lesions with LCIS and residual microcalcifications were excised. Three yielded atypical ductal hyperplasia (ADH); one, residual LCIS; and one, ALH. Three masses with LCIS were excised. One showed residual LCIS; one, a papilloma with adjacent LCIS; and one, a fibroadenoma with LCIS in it. One cluster of microcalcifications was gone at follow-up, and one was stable. CONCLUSION: After a diagnosis of lobular neoplasia at core biopsy, residual microcalcifications are viewed in the context of a patient at higher risk of cancer. Of 11 lesions with residual microcalcifications, three (27%) were ADH and one (9%) was DCIS.

Repeat cervical cytology at the time of colposcopy. Is there an added benefit?

OBJECTIVE: To determine if repeating the Pap smear (PS) at colposcopy offers added benefit in the detection of cervical squamous intraepithelial lesions (SILs). STUDY DESIGN: Eight hundred fifty-two women were subjects of this study. Patients with cervical SIL were defined as women with SIL on the repeat PS, or SIL on the colposcopic cervical biopsy (bx) or a negative repeat PS and bx but confirmed SIL on both the previous and follow-up PS or bx. The sensitivities of repeat PS and bx in detecting SIL were calculated. The chi 2 test was used to assess statistical significance. The total cost of repeating the PS was calculated by multiplying the total number of patients (852) by the estimated cost of a single PS ($25). RESULTS: The sensitivities of repeat PS, bx and PS/bx combined were .89, .69 and .92 for low grade SIL (LSIL) and .74, .77 and .98 for high grade SIL (HSIL), respectively (P < .0001). Sixteen percent of the HSIL and 28% of the LSIL cases were diagnosed on repeat PS only (negative bx). If repeat PS was omitted, $21,300 would have been saved.

Differential diagnosis between monomorphic clear cell adenocarcinoma of salivary glands and renal (clear) cell carcinoma.

Clear cell adenocarcinoma of salivary glands (CCASG) is a relatively rare tumor, composed entirely of clear cells of putative ductal origin. It bears striking morphologic similarities to renal cell carcinoma (RCC) of clear cell type on hematoxylin and eosin stains. Differentiation between CCASG and metastatic RCC to the salivary glands has been considered problematic or even impossible on morphologic grounds. We examined three cases of CCASG and 12 cases of RCC (6 primary and 6 metastatic) by hematoxylin and eosin staining, immunohistochemistry, and electron microscopy. Two distinctive immunohistochemical and ultrastructural patterns emerged from this analysis. CCASG showed positivity for high molecular weight cytokeratin and carcinoembryonic antigen and ultrastructurally showed prominent squamoid differentiation, glycogen pools, and absence of lipid. In contrast, RCC was characterized by positivity for vimentin and complete absence of staining for high molecular weight cytokeratin and carcinoembryonic antigen. On ultrastructural studies, RCC lacked any squamoid differentiation, and the tumor cells contained abundant cytoplasmic lipid in addition to glycogen. Thus, based on the consistent differences on the immunohistochemical staining patterns and their characteristic subcellular morphology, CCASG and RCC can be distinguished on pathologic evaluation. The different direction of differentiation of the cells in CCASG and RCC (i.e., ductal in the former and renal tubular and mesodermal in the latter) results in their distinctive immunophenotypical and ultrastructural features.

Artifact in cervical LLETZ specimens: correlation with follow-up.

The effect of cautery artifact on the ability to accurately diagnose dysplasia and predict abnormal follow-up in large loop excision specimens of the transformation zone (LLETZ) has not been adequately addressed in the pathology literature. One hundred consecutive conization specimens with cytologic and/or histologic follow-up were studied. Indications for the procedure were high-grade squamous intraepithelial lesion (on Pap smear and/or biopsy) in 64 cases, low-grade squamous intraepithelial lesion in 28, atypical squamous cells of unknown significance (ASCUS) in 3, atypical glandular cells of unknown significance in 2, adenocarcinoma in situ, squamous carcinoma in situ, and invasive squamous carcinoma in 1 each. Twenty-four specimens were cold-knife conizations (CKCs) and 76 LLETZs. All LLETZs had at least 1+ artifact, and in 46 cases (61%) it interfered with at least one aspect of evaluation. In 21 cases (28%), 1+ artifact interfered only with margin assessment. In 25 cases (33%), there was 2+ or 3+ artifact precluding not only margin assessment, but also diagnosis and grading of dysplasia. Of the 43 LLETZs received in more than one piece, 33 (77%) had interfering artifact, and in 21 (49%) it was 2+ or 3+, at least focally interfering with diagnosis and grading. In contrast, of 33 LLETZs received in a single piece, only 13 (39%) had interfering artifact, which was 2+ or 3+ in 4 (12%), (p < 0.05). Positive follow-up (including ASCUS, favor dysplasia, and ASCUS, not otherwise specified) was found in 6 of 7 CKCs with positive margins (86%), 10 of 16 LLETZs with positive margins (63%), and 4 of 7 LLETZs with unassessable margins (57%). In cases with negative cone margins, positive follow-up was found in 2 of 17 CKCs (12%), and 18 of 53 LLETZs (34%), p < 0.05; a higher frequency of interfering artifact (p < 0.05) was seen in these cases. LLETZ margin status and postprocedure endocervical curettage (ECC) specimens were not good predictors of residual disease, unlike margin status in CKC. Post-CKC ECC was a better predictor of subsequent abnormal follow-up than post-LLETZ ECC (p < 0.05). The presence of interfering artifact was only rarely mentioned in the original pathology report. In conclusion, the status of margins is a better predictor of abnormal follow-up in CKC than in LLETZ specimens. Fragmentation of the specimen is an additional factor, compounding the inevitable artifact. Postprocedure ECC is not a useful indicator of residual dysplasia. The pathologist should not hesitate to comment on specimen adequacy in surgical pathology reports.

Correlation of proliferation indices, apoptosis, and related oncogene expression (bcl-2 and c-erbB-2) and p53 in proliferative, hyperplastic, and malignant endometrium.

BACKGROUND: The various morphological groupings of endometrial pathology are often difficult to distinguish from each other. The endometrium is an actively proliferating tissue and there is an overlap in cell proliferation fraction (CPF) between benign proliferative endometrium (BPE) and endometrial carcinoma (EC). Apoptosis in benign cycling endometrium is related to the menstrual cycle. In this study we evaluated CPF, apoptosis, and oncogenes that relate to cell turnover (bcl-2, p53, and c-erbB-2) in the spectrum of endometrial pathology. METHODS: We examined a total of 64 cases consisting of 10 cases of BPE, 18 cases of simple endometrial hyperplasia (SEH), 18 cases of complex hyperplasia (CEH; including eight cases with atypical hyperplasia), and 18 cases of EC, FIGO grade 1. CPF was measured by the mitotic index (MI) and by the percentage of Ki-67 positive nuclei (Ki-67 index). Apoptotic index (AI) was determined on hematoxylin and eosin sections. RESULTS: MI was 2.48% in BPE, 0.65% in SEH, 0.6% in CEH, and 0.91% in EC (P < .00001). Ki-67 index was 38.44%, 16.4%, 23.25%, and 31.7% respectively (P < .00001). AI was 1.17%, 2.2%, 2.57%, and 3.31% respectively (P = .02). The AI/MI and AI/Ki-67 ratios were lowest in BPE and highest in SEH (P = .007). All cases of BPE, 84% of SEH cases, 77% of CEH cases, and 88% of EC cases displayed cytoplasmic and/or nuclear bcl-2 expression. Cytoplasmic bcl-2 expression increased from BPE to SEH, whereas it decreased in CEH and EC with emergence of only nuclear expression. Of the EC cases, 38.8% showed intense nuclear bcl-2 reactivity and a significantly higher Ki-67 index than cases with cytoplasmic expression (P = .01). No p53 or c-erbB-2 expression was seen in either BPE or EH. Of the EC cases, 50% were positive for p53 whereas 30% were positive for c-erbB-2. C-erbB-2-positive cases had a significantly higher Ki-67 index and AI than negative cases (P = .02). Cases of EC with p53 expression also had significantly higher AI (P = .01). CONCLUSIONS: In actively proliferating tissues like endometrium, CPF does not correlate with progression to malignancy. In contrast, AI and derived AI/CPF ratios are better indicators of progression. The expression of p53, c-erbB-2, and nuclear bcl-2 in EC correlate with higher cell turnover indices (CPF and AI).

Mammographic-histopathologic correlation of large-core needle biopsies of the breast.

Large-core (14g) needle biopsy (CNB) of the breast is a new diagnostic modality increasingly being used to evaluate patients with mammographic abnormalities. Two hundred twenty-four CNBs were performed on 198 patients. Surgical follow-up was available in 64 cases (28.6%). Overall concordance rate was 93.8% (60 of 64 cases). Of the four discordant cases, two were diagnosed as atypical ductal hyperplasia (ADH) on CNB; on excision, these cases showed cribriform ductal carcinoma in situ (DCIS); two remaining cases, diagnosed on CNB as ADH versus DCIS, showed invasive carcinoma (DCIS with invasive component and infiltrating cribriform carcinoma, respectively) on excisional biopsy. Malignancy, primary (52) or metastatic (5), was identified in 57 cases (25.4%); 47 of these patients underwent surgical excision, and the diagnosis was confirmed in all of these cases. Of 51 cases with radiographic evidence of microcalcifications, 48 (94%) had microcalcifications in the CNB: 30 (62.5%) were benign, 11 (22.9%) were malignant, and 7 (14.6%) were diagnosed as ADH. In the remaining three cases (1.3%), only benign breast tissue without microcalcifications was seen, and the lesion was considered to have been missed. Biopsy specimens were obtained from 173 lesions because of the presence of a mass: 125 (72.3%) were benign, 45 (26%) were malignant, and 3 (1.7%) were diagnosed as ADH. Follow-up was available in 118 patients with benign lesions: all were mammographically stable or decreased at 6 or 12 months; no follow-up was available for the remaining patients. CNB of the breast is a highly sensitive (96.9%) and specific (100%) technique for management of patients with mammographic abnormalities. The histologic findings should be correlated with the mammographic appearance, and an attempt should be made to achieve a specific diagnosis in all lesions, particularly masses. The diagnosis of ADH should always prompt excisional biopsy because of a high frequency of false-negative results caused by sampling errors or underestimation.

Cloacal dysgenesis sequence: observations in four patients including three fetuses of second trimester gestation.

Cloacal dysgenesis is a rare malformation sequence. We studied cloacal dysgenesis in four fetuses, including three at 18-22 weeks of gestation. All four fetuses showed a smooth perineum with absence of anal, urethral, and/or vaginal openings. The urinary bladder was dilated in 3 cases. The labia majora and minora were absent in the two female fetuses; the scrotum and penis were absent in one male fetus and hypoplastic in the second. The kidneys were either absent (1 case), dysplastic (1 case), or hydronephrotic (1 case). Normal kidneys were seen in a fetus of 20-22 weeks gestation in whom the urinary obstruction was alleviated by a vesicocolonic fistula. This fetus did not have pulmonary hypoplasia. Severe renal anomaly and pulmonary hypoplasia are the limiting factors for the survival of infants born with cloacal dysgenesis. The unique observation of normal kidneys and lungs in one of our fetuses, despite anhydramnios, suggests that the effect of oligohydramnios on lung development may be limited early in gestation, at least up to 20-22 weeks. It may also indirectly support the theory that there are factors other than oligohydramnios that interfere with early lung development, such as reduced production of a pulmonary growth factor by the kidney or reduced proline production by malformed kidneys, that may cause decreased collagen formation and result in hypoplastic lung mesenchyme.

Progressive increase of apoptosis in prostatic intraepithelial neoplasia and carcinoma: comparison between in situ end-labeling of fragmented DNA and detection by routine hematoxylin-eosin staining.

OBJECTIVE: Apoptosis has attracted significant attention in the study of tumors during recent years. The first goal of this study was to evaluate the number of apoptotic cells and bodies in benign glands, in high-grade prostatic intraepithelial neoplasia, and in malignant prostatic glands. The second objective was to compare the effectiveness of in situ end-labeling of fragmented DNA (ISEL) with the use of routine hematoxylin-eosin (H&E) stains in the assessment of apoptosis rates. METHODS: The percentage of apoptosis was measured with ISEL and H&E stains in sections from 16 prostatectomies performed for previously untreated peripheral prostatic adenocarcinomas. RESULTS: Both methods showed progressive increase of the rates of apoptosis from benign glands (0.34% to 0.38%), to high-grade prostatic intraepithelial neoplasia (1.44% to 1.39%), to carcinoma (2.69% to 2.75%). The increase in apoptosis rate in prostatic intraepithelial neoplasia and carcinomas is one more indication of the continuum in the pathogenetic process leading to invasive prostatic carcinoma. Student's t test revealed no statistically significant difference in the percentage of apoptosis rendered by ISEL and H&E staining. CONCLUSIONS: From a practical point of view, evaluation of apoptosis with H&E stains can be readily performed using routine clinical material. The procedure is inexpensive, and it gives good tissue morphology. However, quantitative measurements may be time-consuming and observer-dependent. The apoptotic bodies are clearly identifiable with ISEL, making quantitation easy and even amenable to automated counting methods. Disadvantages of ISEL are significantly higher costs and poor tissue morphology. We conclude that accurate evaluation of apoptosis may be performed reliably with both routine H&E staining and the ISEL method. The decision to choose one method over the other depends on the economic resources available and the amount of material to be evaluated.

Comparative study of invasive squamous cell carcinoma and verrucous carcinoma of the oral cavity: expression of bcl-2, p53, and Her-2/neu, and indexes of cell turnover.

Significant clinical and biological differences are found between invasive squamous cell carcinoma (SCCA) and verrucous carcinoma (VC) of the oral cavity. The correct diagnosis of these tumors has important therapeutic implications. Immunoperoxidase stains for bcl-2, p53, and Her-2/neu, and in situ end-labeling of DNA to identify apoptosis were performed in eight VC and eight SCCA matched for age, sex, and stage. Marked differences were identified in the pattern of expression of oncogenes and the indexes of cell turnover in these two types of tumors. VC displayed minimal apoptosis in rare keratinizing cells (0 to 3%); p53-positive cells (4/8) and Ki-67 (8/8) were confined to the nuclei of the basal proliferating layers; and bcl-2 (4/8) was expressed only in the cytoplasm of rare tumor cells. In contrast, SCCA displayed higher apoptosis rates (5 to 10%), whereas p53- (5/8) and Ki-67- (8/8) positive nuclei were distributed randomly throughout the tumor. Very well differentiated areas in one SCCA case had a pattern of staining for p53 and Ki-67 similar to the one seen in VC. In SCCA bcl-2 showed patchy cytoplasmic staining (4/8) or strong cytoplasmic and nuclear positivity (2/8) in the less differentiated tumors. Her-2/neu was negative in all VC and SCCA cases. The different levels and patterns of gene expression and cell turnover between SCCA and VC undoubtedly correlate with the different biology and prognosis of these tumors.